PIKfyve, MTMR3 and their product PtdIns5P regulate cancer cell migration and invasion through activation of Rac1

Recently, we have shown that the phosphoinositide metabolizing enzymes PIKfyve and MTMR3, together with their lipid product phosphatidylinositol 5-phosphate (PtdIns5P), are important for migration of normal human fibroblasts. As these proteins are a kinase and a phosphatase, respectively, and thereby considered druggable, we wanted to test their involvement in cancer cell migration and invasion. First, we showed that PIKfyve and MTMR3 are expressed in most cancer cells. Next we demonstrated that depletion of PIKfyve or MTMR3 resulted in decreased velocity in three different cancer cell lines by using new software for cell tracking. Inhibition of the enzymatic activity of PIKfyve by the inhibitor YM201636 also led to strong reduction of cell velocity. Mechanistically, we show that PIKfyve and MTMR3 regulate the activation of the Rho family GTPase Rac1. Further experiments also implicated PtdIns5P in the activation of Rac1. The results suggest a model for the activation of Rac1 in cell migration where PIKfyve and MTMR3 produce PtdIns5P on cellular membranes which may then serve to recruit effectors to activate Rac1. Finally, in an invasion assay, we demonstrate that both PIKfyve and MTMR3 are implicated in invasive behaviour of cancer cells. Thus, PIKfyve and MTMR3 could represent novel therapeutic targets in metastatic cancer.

Source: BJ Cell - May 19, 2014 Category: Biochemistry Authors: A Oppelt, E Margrethe Haugsten, T Zech, H E Danielsen, A Sveen, V H Lobert, R I Skotheim, J Wesche Tags: BJ Cell Source Type: research